The most frequently encountered immunodeficiency-related LPDs are those occurring in the setting of HIV-infection (HIV-related lymphomas account for approximately 10% of all lymphomas diagnosed in the United States and Europe) and following organ transplantation. These lesions, because of their frequency, have been better characterized and thus will be the focus of this presentation. The primary immune disorders and methotrexate-related LPDs are relatively rare and therefore have not been as extensively studied.

HIV-RELATED LYMPHOMA:
Approximately 1 year after the initial AIDS cases were reported, young immunocompromised homosexual men presenting with advanced Burkitt's lymphoma were described in the literature. Within 5 years the CDC expanded its criteria to include intermediate and high grade B-cell or null-cell lymphoma occurring in an HIV-seropositive individual as an AIDS defining illness. Non-Hodgkin's lymphoma (NHL) is now the second most common AIDS-related malignancy in HIV-positive individuals and is the most common tumor occurring in IVDUs and hemophiliacs. The incidence of NHL in HIV positive individuals is estimated to be between 4 and 10%. The development of these lesions is complex and is thought to be related to disrupted immune surveillance (as exemplified by the correlation of a decreased CD4 count and the increased risk of some types of NHL), chronic antigenic stimulation, genetic alterations, cytokine dysregulation and herpes virus infection.

Although phenotypically HIV-related NHLs are virtually always of B cell origin (greater than 90%), they are morphologically diverse. Many of the NHLs are similar to lymphomas occurring in immunocompetent patients, while others preferentially develop in AIDS patients. HIV-related lymphomas can be classified based on morphology (as in the WHO classification), however, these lymphomas can also be classified based on primary site of presentation.

WHO CLASSIFICATION: MORPHOLOGIC CATEGORIES OF HIV-ASSOCIATED LYMPHOMAS
(Modified – B Cell Lymphomas)

Lymphomas also occurring in immunocompetent patients Burkitt's lymphoma (BL; see below) Diffuse large B-cell lymphoma Centroblastic (CB) Immunoblastic (IB) Rare - Extranodal marginal zone B-cell lymphoma of MALT-type Lymphomas occurring primarily in HIV-positive patients Primary effusion lymphoma (PEL) - rare Plasmablastic lymphoma of the oral cavity - very rare KSHV-associated extracavity lymphoma (not in WHO classification) - not defined Lymphomas occurring in other immunodeficiency states Polymorphic B-cell lymphoma (PT-LPD-like)

Lymphomas also occurring in immunocompetent patients:
These NHLs should be morphologically classified based on criteria used for immunocompetent patients.

Burkitt's lymphoma (BL):
HIV-related BL accounts for approximately 40% of all systemic HIV-related NHL and includes cases exhibiting the features of classical BL, those showing plasmacytoid differentiation and those exhibiting features of atypical Burkitt's/Burkitt's-like lymphoma. The morphologic variant of BL with plasmacytoid differentiation is relatively unique to HIV-related NHLs. The cells show more cytologic variability with respect to size and shape than classical BL. Furthermore, the nuclei in this subtype of BL are often larger than histiocyte nuclei and may exhibit immunoblastic features. The cells may contain cytoplasmic immunoglobulin.

Immunophenotypically and genetically all morphologic forms of BL are similar: they express pan B-cell antigens such as CD19 and CD20 and are CD10 and BCL6 positive. Nearly 100% of the cells express the proliferation-associated marker Ki-67 (MIB-1). Between 25-75% of cases are EBV positive based on in situ hybridization, but do not express the EBV transforming proteins LMP-1 or EBNA2 (table 1). The vast majority of cases contain a c-myc rearrangement. A significant number of cases also contain mutations in the p53 gene. These p53 mutations are seen in the c-myc rearranged cases. Although only a small number of cases contain bcl-6 gene rearrangements, a significant number of cases contain mutations in the 5' non-coding region of the gene (table 2).

Patients with BL tend to be younger (median age 35 in one study) with relatively higher CD4 counts (table 3). Only occasionally have the patients had a previous AIDS-defining diagnosis. This HIV-related NHL involves the bone marrow (35-40% of cases) more frequently than the other common types of systemic HIV-related lymphomas (i.e. DLCL-CB and DLCL-IB). The 2-year survival for HIV-positive patients with BL is approximately 32%.

Diffuse large B-cell lymphoma-centroblastic (CB):
These tumors contain a large number of centroblasts admixed with a variable number of immunoblasts. Some cases may be very polymorphic in appearance containing cells with cleaved or multilobated nuclei. Immunophenotyically the tumor cells express B cell associated antigens and are usually BCL6 positive; a proportion may be CD10 positive. Only approximately 20-40% of cases are EBV positive and unless the tumor is a primary CNS lymphoma lack expression of LMP-1 (table 1). These NHLs may occasionally exhibit rearrangement of the bcl-6 gene, but often contain mutations in the 5' regulatory region of the bcl-6 gene. Random cases will also exhibit alterations in the ras and c-myc genes (table 2). These lymphomas account for approximately 30% of all systemic HIV-related lymphomas.

Clinically the patients present with widespread disease that usually involves on or more extra-nodal sites (table 3). The patients have intermediate CD4 counts compared to patients presenting with BL and IB; only occasionally have the patients had a previous AIDS-defining disease. The 2-year survival for patients with systemic CB HIV-related lymphoma is similar to that of patients with BL (31%).

Diffuse large B-cell lymphoma-immunoblastic (IB):
These tumors account for approximately 30% of systemic HIV-related NHLs. These cases contain a large number of immunoblasts (approaching 90%) and often exhibit plasmacytoid features. The cells are large with round, oval or ovoid nuclei and a single prominent nucleolus. Usually a relatively high mitotic rate is identified. In some instances the tumor cells have features reminiscent of Reed-Sternberg cells or variants. These tumors are often EBV positive and express LMP1 (table 1). Most tumors express a variable number of pan B-cell antigens and are CD138 positive; some may be CD30 positive. Although a significant number of cases contain bcl-6 gene mutations, in general most cases lack structural alterations of known oncogenes and tumor suppressor genes (table 2).

Patients with HIV-related IB are usually significantly immunosuppressed with low CD4 counts (median 81 x10⁶/L) and approximately one-third have been diagnosed with an AIDS-defining illness. These patients tend to do poorly with a 2-year median survival of 15% (table 3).

Lymphomas occurring primarily in HIV-positive patients: These NHLs occur primarily in HIV-positive individuals and only rarely in immunocompetent patients.

Primary effusion lymphoma (PEL):
Primary effusion lymphoma (PEL) was initially described as a distinct entity in 1995 by Cesarman, et al, based the identification of the Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) within the tumor cells. Primary effusion lymphomas rare tumors, accounting for only approximately 3% of all HIV-related NHLs. The neoplasm presents as an effusion usually involving one or more of the pleural, abdominal and pericardial spaces without a tissue mass.

Primary effusion lymphoma cells are morphologically composed of large, pleomorphic cells exhibiting features which bridge those of immunoblastic lymphoma and anaplastic lymphoma. The cells have large nuclei with prominent nucleoli and a moderate to abundant amount of amphophilic to basophilic cytoplasm. A variable number of cells will have features reminiscent of Reed-Sternberg cells or are "wreath" – like; still others are have highly irregular lobated nuclei imparting a "jelly-fish" like appearance.

Immunophenotypically PELs cells express CD45, but usually lack expression of B and T cell lineage associated antigens; some cases, however, have been reported to express surface or cytoplasmic immunoglobulin. The cells express a variety of activation associated antigens including CD30, CD38, CD71 and epithelial membrane antigen (EMA). The cells are usually CD138 (syndecan-1) and MUM1/IRF4 positive, but lack expression of BCL-6. Furthermore, by immunohistochemistry the tumor cells are positive for KSHV latent nuclear antigen (LANA; LNA-1) and a small proportion of the cells (approximately 5-10%) express viral interleukin-6 (vIL6). Expression of this viral cytokine is thought to be important in the pathogenesis of PEL. All cases contain KSHV and approximately 80% of cases contain EBV; however the tumor cells lack expression of the EBV transforming protein LMP-1 (table 1). The PELs appear to only rarely contain structural alterations in the major oncogenes and tumor suppressor genes, such as c-myc, H-, K-, N-ras and p53, but do contain mutations in the non-coding region of thebcl-6 gene (table 2).

Patients diagnosed with PEL are usually HIV-positive homosexual males in their early 40s with low CD4 counts and/or a previous history of an opportunistic infection. The median CD4 count at diagnosis is approximately 80 x 10⁶/L. The patients have an aggressive clinical course with a median survival of less than 6 months (table 3).

KSHV-positive extra-cavity NHLs:
A recently described unique lymphoma known as plasmablastic lymphoma (not to be confused with plasmablastic lymphoma of the oral cavity which is KSHV negative, but often EBV positive) occurs primarily in patients with KSHV-related multicentric Castleman's disease. These plasmablastic lymphomas are KSHV positive, EBV negative, express high levels of immunoglobulin, are only weakly CD30 positive and do not contain mutations in the immunoglobulin genes. These lymphomas are thought to arise from naïve IgM lambda expressing B cells rather than terminally differentiated B cells as is the case with PELs. In addition, rare reports of HIV-related KSHV-positive pleomorphic NHLs occurring in solid tissues, without an effusion, but with immunophenotypic and genotypic profiles similar to PELs have been described.

Polymorphic B-cell lymphoma (PT-LPD-like):
These are extremely rare lesions but morphologically resemble polymorphic PT-LPDs (see below). Morphologically the lesions are composed of a polymorphic cell population ranging from small lymphocytes, often with plasmacytoid features, to large, transformed cells that often have features reminiscent of Reed-Sternberg cells. Approximately 40% of these lesions contain EBV. Most, but not all of these proliferations contain clonal rearrangement of an immunoglobulin gene (tables 1 and 2). In general, and similar to polymorphic PT-LPDs, the lesions lack structural alterations in oncogenes and tumor suppressor genes.

HIV-RELATED LYMPHOMA CLASSIFICATION BASED ON LOCATION

• Systemic lymphomas (nodal and extra-nodal): 85-90% of HIV-NHLs; see above
• Primary CNS lymphomas: 10-15% of HIV-related NHLs; see below
• Primary effusion lymphomas: 3% of HIV-related NHLs; see above

Primary CNS lymphomas:
Lymphomas occurring primarily in the CNS are different from those occurring systemically; the clinical features of the patients developing these lesions are also different. In comparison to systemic HIV-related lymphomas, the majority of the cases exhibit IB morphology and only relatively rarely are classified as BL. Furthermore, over 90% of the NHLs are associated with EBV infection and express LMP-1; the majority of cases also express EBNA2. In addition, the tumors are often CD138 positive (consistent with their IB morphology) and lack structural alterations in oncogenes and tumor suppressor genes. The patients tend to be older (approximately 40 years of age) and severely immunosuppressed at presentation (mean CD4 count of less than 50 x10⁶/L); most patients have been previously diagnosed with an AIDS-defining illness. The median survival of patients with AIDS-related primary CNS lymphoma diagnosed prior to autopsy is less than 6 months.

POST-TRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS:
Post-transplantation lymphoproliferative disorders (PT-LPDs) develop in the setting of iatrogenic immunosuppression following solid organ or allogeneic bone marrow transplantation (BMT). The incidence of these lesions varies based on the type of organ transplanted as well as on the type and amount of immunosuppression employed (table 4a).

In solid organ recipients the incidence of PT-LPD is relatively low in patients who have received renal transplants (approximately 1%), but is higher in those who have undergone heart or heat-lung transplantation. Furthermore, solid organ transplant recipients who have received immunosuppressive regimens that include cyclosporine A and/or monoclonal antibody OKT3 are at an increased risk for PT-LPD. The risk factors for patients who have undergone allogeneic BMT are somewhat different, but include T cell depletion of the donor marrow, severe graft-vs.-host disease, anti-thymocyte immunotherapy and HLA-mismatch of donor and recipient (2 or more antigens). The pathogenesis, however, of PT-LPDs developing in solid organ and bone marrow transplant recipients is different since those occurring in solid organ recipients are usually of recipient origin while those in bone marrow transplant recipients are usually of donor origin.

In these immunosuppressed patients morphology does not accurately predict clinical course. In some solid organ transplant recipients a lesion may regress completely following a reduction in immunosuppression, while morphologically similar lesion(s) in another patient may progress, in spite of aggressive clinical intervention, resulting in the patient's demise. Furthermore, institution of the correct therapy in these patients is crucial since a reduction in immunosuppression can potentially result in organ loss while chemotherapy can lead to life-threatening infection in an already immunosuppressed individual. Although in some studies specific molecular events correlate well with biologic aggressiveness of the lesions, in other studies these findings cannot be confirmed. It may be that differences in the type of organ transplanted, the immunosuppressive regimens as well as host/donor factors influence the pathogenesis and biologic behavior of PT-LPDs. However, at significant number of patients with solid organ PT-LPDs have regression or resolution of their disease. In contrast, patients who develop PT-LPDs following allogeneic BMT usually have an aggressive, frequently fatal, clinical course. As with other immunodeficiency related LPDs, the development of PT-LPDs in both solid organ and bone marrow transplant recipients is highly associated with EBV infection. Furthermore, the relative incidence of these lesions is higher patients who are EBV negative at the time of transplantation.

PT-LPDs arising in solid organ transplant recipients: Extensive studies of PT-LPDs occurring in solid organ transplant recipients (primarily heart, kidney and lung recipients) have shown that most of these lesions can be separated into three categories based on morphologic and molecular – genetic criteria. These categories in general correlate with biologic behavior of the lesions. Because of the special clinical setting, i.e. that of iatrogenic immunosuppression that can be modulated, a unique classification scheme was developed by Nalesnik, et al, to describe the clinical course and outcome of solid organ PT-LPDs patients.

*modified from Nalesnik, et al (Am J Pathol 1998; 133:173)

Plasmacytic hyperplasia (PH) / infectious mononucleosis-like (table 5):
These lesions show retention of the overall architecture of the tissue. In lymphoid tissue there is usually expansion of the interfollicular area. Germinal centers may be hyperplastic, involuted or absent. The lesions are composed of a mixed lymphoid population consisting primarily of lymphocytes, plasmacytoid lymphocytes, plasma cells and scattered immunoblasts; however, little or no cytologic atypia is present.

Genotypically these lesions in general are polyclonal lesions based on immunoglobulin rearrangement studies. The majority of cases are EBV positive, but exhibit variable clonality (i.e. are polyclonal, oligoclonal or monoclonal). These lesions do not contain structural alterations of oncogenes or tumor suppressor genes. Furthermore, examination of EBV antigen expression shows that these lesions express the LMP1 and in some instances EBNA2 indicating they exhibit either the latency type II or III pattern of EBV gene expression.

Clinically these lesions tend to occur in younger patients, often children or individuals who are EBV negative prior to transplantation (table 6). The lesions can occur at any anatomic site, but tend to involve the head and neck region. These lesions are clinically "non-aggressive". Specifically, the lesions usually regress following a reduction in immunosuppression or can be completely surgically excised (table 7).

Polymorphic PT-LPD (Poly; table 5):
There is destruction of the underlying architecture of the tissues involved by polymorphic PT-LPDs. The lesions are composed of a polymorphic (or heterogeneous) cell population. The lesions vary from those that show extensive plasmacytic differentiation and minimal cytologic atypia to proliferations that lack plasmacytic differentiation and contain atypical immunoblasts; usually a variable number of irregular and "cleaved" cells may be present. Individual cell necrosis to large areas of coagulative necrosis may be present.

At the genetic level these lesions are monoclonal based both on immunoglobulin studies and the presence of clonal EBV. Polymorphic PT-LPDs lack structural alterations in oncogenes and tumor suppressor genes except for the presence of bcl-6 gene mutations which have been identified in approximately half of the cases studied. Lesions containing the wild-type configuration of the bcl-6 gene regress following a reduction in immunosuppression, while those lesions containing bcl-6 gene mutations exhibit more aggressive behavior requiring clinical intervention for potential resolution of the PT-LPD lesions (table 8). Polymorphic PT-LPDs, like the PHs, exhibit the latency type II or III pattern of EBV gene expression.

Similar to their morphology, the clinical course of the patients who develop these lesions is also heterogeneous (tables 6 and 7). In some instances, including some patients with lesions that contain a large number of atypical immunoblasts, the proliferations regress following a reduction in immunosuppression. However, in other instances the polymorphic lesions are aggressive, requiring chemotherapy and/or radiation therapy for potential resolution of the disease. Polymorphic PT-LPDs tend to occur in extranodal sites, often in the gastrointestinal tract and lung.

Monomorpic PT-LPD (malignant lymphoma/multiple myeloma; table 5):
These lesions are composed of cytologically malignant cells. These lesions should be classified according to the WHO classification.

These lesions are monoclonal based both on immunoglobulin and EBV studies. These lesions, however, contain structural alterations in oncogenes and tumor suppressor genes such as p53 and c-myc. In contrast to the other solid organ PT-LPDs these lesions exhibit the latency type I pattern of EBV gene expression.

The patients who develop these lesions have an aggressive clinical course, often with progressive disease that leads to their demise in site of aggressive clinical intervention (tables 6 and 7). The patients also tend to be older. These lesions tend to present in lymph nodes and bone marrow.

Clinical outcome – Correlation with molecular-genetic composition (table 5) :
The PHs are morphologically bland non-clonal lymphoid proliferations based on immunoglobulin gene studies and are often polyclonal or oligoclonal based on the number of EBV infectious events. Furthermore, these lesions do not contain structural alterations in known oncogenes or tumor suppressor genes suggesting they have not undergone neoplastic transformation. These lesions express EBV latency II or III antigens and frequently regress following a reduction in immunosuppression. These findings suggest that reconstitution of the immune system by a reduction in immunosuppression re-establishes the patients immune functions allowing for containment of the EBV infection by T cells. In contrast, the monomorphic PT-LPDs are clonal proliferations that contain structural alterations in oncogenes and tumor suppressor genes indicative of neoplastic transformation. These lesions do not express any EBV transforming genes, suggesting that they are no longer driven by EBV thereby implying that their biological behavior is controlled by genetic events. These lesions are clinically aggressive often resulting in significant morbidity and mortality for the patients. The polymorphic lesions are not clearly malignant based on morphologic or genetic criteria. Although they are monoclonal, they do not always contain structural alterations in known oncogenes and tumor suppressor genes indicating complete neoplastic transformation. Furthermore, these lesions express EBV transforming genes, suggesting that they are at least partially driven by this virus. Reflecting the genetic composition and infectious status of the lesions, the clinical course of the patients may be either non-aggressive or aggressive. However, the presence of absence of mutations in the non-coding regulatory region of the bcl-6 gene highly correlates with the biologic behavior of the solid organ PT-LPDs (table 8). Specifically, lesions exhibiting the wild-type configuration usually will regress following a reduction in immunosuppression while those containing bcl-6 mutations lesions are aggressive lesions requiring chemotherapy and/or radiation therapy for potential resolution of the disease process. Thus, it appears that the genetic composition of the lesions dictates the clinical behavior of the solid organ PT-LPDs.

Furthermore molecular studies have also shown that anatomically separate, morphologically similar lesions occurring in the same patient may exhibit a completely different genetic composition. Thus, PT-LPD should be thought of as a multi-clonal disease process requiring genetic analysis of as many lesions as possible to accurately diagnose and treat the patient.

PT-LPDs in allogeneic bone marrow recipients:
PT-LPDs occurring in allogeneic BMT recipients are biologically distinct from those occurring in solid organ transplant recipients. BMT PT-LPDs are of donor origin, often have an explosive clinical presentation and are frequently fatal. Furthermore, BMT PT-LPDs tend to occur in the first six months following transplantation, since it takes approximately 6 months after transplantation for the level of anti-EBV cytotoxic T cell precursors to return to normal. In comparison to solid organ PT-LPDs the incidence of BMT PT-LPD is relatively low (cumulative incidence of 1% at ten years). As with solid organ PT-LPDs the vast majority of cases are associated with EBV infection.

Morphologically BMT PT-LPDs consist of lesions exhibiting the histologic features of PH and polymorphic PT-LPD as seen in the solid organ transplant recipients. However, none of the PT-LPDs we studied from 27 allogeneic BMT recipients showed the morphologic features of monomorphic PT-LPD, although other investigators have identified such lesions occurring a year or more following transplantation. Although morphology did correlate with clinical outcome, B cell clonality, based only on PCR analysis of the early onset PT-LPDs we studied, did not correlate with morphology nor did it correlate with clinical outcome. Specifically, patients with both monoclonal/oligoclonal as well as those with polyclonal PT-LPDs died of PT-LPD. Examination of the BMT PT-LPDs for bcl-6 mutations also did not identify any correlation of this genetic alteration with patient outcome (table 9).

However, all BMT PT-LPDs exhibited EBV latency patterns type II or III (expressed LMP-1 with or without EBNA2) indicating that these lesions are EBV driven. Thus, the clinical outcome of these patients is related to the number and competence of EBV-specific cytotoxic T cells. However, only 38% of patients with lesions exhibiting latency type II compared to 92% of those with lesions exhibiting latency type III died of PT-LPD raising the possibility that more than one EBV gene product is involved in the pathogenesis of these lesions.

Pathologic findings correlating with clinical outcome in PT-LPD patients differ depending on whether they have received a allogeneic bone marrow or solid organ transplant (table 10). In the BMT recipients morphology and EBV status correlates with a poor clinical outcome while in solid organ transplant recipients clinical outcome correlates more closely with the genetic composition of the tumor and not with EBV status (table 10). Specifically, in the BMT recipients polymorphic morphology and EBV positivity (and EBV latency III gene expression pattern) correlate with death due to PT-LPD while in solid organ transplant recipients genetic defects such as bcl-6 and p53 mutations are associated with aggressive clinical behavior and potentially death due to PT-LPD.

UNCOMMON CLINICAL SETTINGS ASSOCIATED WITH LYMPHOPROLIFERA-TIVE DISORDERS:
These include LPDs associated with (1) primary immune disorders (PIDs) and (2) methotrexate.

Lymphoproliferative disorders associated with primary immune disorders (PIDs) :
The development of PID-associated LPDs is related to a variety of specific genetic defects including those involving cytokine production, signal transduction pathways and cell adhesion involved in normal immune function and surveillance. The type of lymphoma developed in each clinical setting is influenced by the underlying genetic defect. Thus, although the vast majority of cases are associated with EBV infection, the morphologic, immunophenotypic and genotypic features of PID LPDs are highly variable. The majority of PID LPD patients develop diffuse large B-cell lymphoma with more cases showing IB than CB features. There is also an increased incidence of lymphomatoid granulomatosis in some patients, particularly those with the Wiskott-Aldrich syndrome, which may progress over time to DLCL. Other types of B cell lymphoma, Hodgkin lymphoma, T cell lymphomas as well as fatal infectious mononucleosis have been described to occur in these patients. As with other immunodeficiency related LPDs, these lesions usually occur in extanodal sites.

Methotrexate-associated lymphoproliferative disorders (MXT-LPDs):
These lesions are extremely rare. The majority of these cases have been described in patients with rheumatoid arthritis (RA); a small percentage of cases have been also described in patients with dermatomyositis and psoriasis. However, as patients with RA are already at an increased risk for the development of NHL, whether methotrexate therapy per se is associated with the development of lymphoma in these patients has not been clearly delineated. Many cases present in extranodal sites. The majority of the reported cases are diffuse large B-cell lymphoma or Hodgkin lymphoma.

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